Tumor necrosis factor alpha (TNF-α) converting enzyme (TACE) or ADAM 17 (a disintegrin and metalloprotease), a member of a family of zinc metalloproteases, is an important regulator of inflammation, immune regulation, and cellular proliferation as a consequence of its ability to process integral cell surface proteins to soluble forms (Moss et al., Drug Discov. Today, 6:417 (2001); Black, Int. J. Biochem. Cell. Biol., 34:1 (2002); Moss et al., Cell, 90:589 (1997)). TACE was originally identified as the enzyme that cleaves the membrane-bound precursor of tumor necrosis factor-alpha (TNF-α) (Moss et al., Drug Discov. Today, 6:417 (2001); Moss et al., Nature, 385:733 (1997); Black et al., Nature, 385:729 (1997)). Other cell surface proteins that have been identified as substrates for TACE include L-selectin (Peschon et al., Science 282:1281 (1998)), transforming growth factor-α, TNF receptors I and II (Peschon et al., Science, 282:1281 (1998); Reddy et al., J. Biol. Chem., 275:14608 (2000)), interleukin-6 receptor-α (Althoff et al., Eur. J. Biochem., 267:2624 (2000)), interleukin-1 receptor II (Reddy et al., J. Biol. Chem., 275:14608 (2000)), Notch1 receptor (Brou et al., Mol. Cell., 5:207 (2000)), TNF-related activation-induced cytokine (TRANCE) (Schlondorff et al., J. Biol. Chem., 276:14665 (2001)), amyloid precursor protein (Buxbaum et al., J. Biol. Chem., 273:27765 (1998)), fractalkine (CX3CL1) (Garton et al., J. Biol. Chem., 276:37993 (2001)), CD30 (Hansen et al., J. Immunol., 165:6703 (2000)), CD40 (Contin et al., J. Biol. Chem., (2003)), macrophage colony stimulating factor receptor (Rovida et al., J. Immunol., 166:1583 (2001)), cellular prion protein (Vincent et al., J. Biol. Chem., 276:37743 (2001)), MUC1 (Thethiah et al., J. Biol. Chem., 278:3386 (2003)), growth hormone binding protein (Zhang et al., Endocrinology 141:4342 (2000)), erbB4/HER4 (Rio et al., J. Biol. Chem., 275:10379 (2000)), pro-heparin binding EGF-like growth factor (Merlos-Suarez et al., J. Biol. Chem., 276:48510 (2001)), and amphiregulin (Sunnarborg et al., J. Biol. Chem., 277:12838 (2002)).
ADAM family zinc metalloproteases, including TACE, typically have a conserved structure that includes a signal sequence, prodomain, metalloprotease domain, disintegrin domain, cysteine-rich domain containing an epidermal growth factor-like repeat, a transmembrane domain and an intracytoplasmic tail (Moss et al., Drug Discov. Today, 6:417 (2001); Moss et al., Nature, 385:733 (1997); Black et al., Nature, 385:729 (1997); Schlondorff et al., Biochem. J., 347:131 (2000); Schlondorff and Blobel, J. Cell. Sci., 112:3603 (1999)). The function of the prodomain is to retain the proenzyme in an inactive state via a cysteine switch mechanism, whereby a cysteine in the prodomain coordinates with a zinc molecule in the catalytic site (Van Wart and Birkedal-Hansen, Proc. Natl. Acad. Sci. USA, 87:5578 (1990)). The TACE prodomain may also play an important role in protein folding, as TACE mutants lacking the prodomain are inefficiently synthesized in insect cells, suggesting intracellular degradation (Milla et al., J. Biol. Chem., 274:30563 (1999)). Removal of the TACE prodomain occurs in the late Golgi compartment and can be mediated by furin and other proprotein-convertases, such as PC7 (Schlondorff et al., Biochem. J., 347:131 (2000); Endres et al., Eur. J. Biochem., 270:2386 (2003); Borroto et al., J. Biol. Chem., 278:25933 (2003); Peiretti et al., Exp. Cell. Res., 285:278 (2003)). Mutant cell lines with impaired intracellular trafficking of TACE to the Golgi compartment have been described (Borroto et al., J. Biol. Chem., 278:25933 (2003)). These cells accumulate full-length, inactive protein within the endoplasmic reticulum and demonstrate a gross defect in ectodomain shedding. Stimulation with phorbol ester, a potent inducer of cell surface shedding, induces internalization and degradation of TACE from the plasma membrane and impairs TACE prodomain cleavage and maturation (Endres et al., Eur. J. Biochem., 270:2386 (2003); Doedens et al., J. Biol. Chem., 275:14598 (2000)).
The action of TNF-α has been implicated in such diseases as arthritis, sepsis, ulcerative colitis, multiple sclerosis, Crohn's disease, septic shock, graft rejection, cachexia, insulin resistance, post-ischemic reperfusion injury, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss, demyelinating diseases of the nervous system, and HIV infection. Accordingly, agents, compositions, and methods that can be used to increase or decrease the activity of TNF-α converting enzyme are needed.